Hypercholesterolemia is an established risk factor in the development of atherosclerosis. Therapeutic agents which control the level of serum cholesterol have proven to be effective in the treatment of coronary artery disease. While agents exist that can modulate circulating levels of cholesterol carrying lipoproteins, these agents have little or no effect on the intestinal absorption of cholesterol. Dietary cholesterol can increase the level of serum cholesterol to levels which place an individual at increased risk for the development or exacerbation of atherosclerosis. Since much of the free or unesterified cholesterol that is absorbed by intestinal mucosal cells must first be esterified by ACAT prior to its incorporation and secretion into the bloodstream in large lipoprotein particles called chylomicrons, inhibition of ACAT can reduce the absorption of dietary cholesterol. In addition, the accumulation and storage of cholesteryl esters in the arterial wall is associated with increased activity of ACAT. Inhibition of the enzyme is expected to inhibit the formation or progression of atherosclerotic lesions in mammals.
There is an increasing number of patents in the literature disclosing compounds which are useful as ACAT inhibitors in particular and antiatherosclerotic agents in general. For example, U.S. Pat. No. 4,623,662, issued to De Vries on Nov. 18, 1986, discloses ureas and thioureas as ACAT inhibitors useful for reducing the cholesterol ester content of an arterial wall, inhibiting atherosclerotic lesion development, and/or treatment of mammalian hyperlipidemia. U.S. Pat. No. 4,722,927, issued to Holmes on Feb. 2, 1988, discloses disubstituted pyrimidineamides of oleic and linoleic acids as ACAT inhibitors useful for inhibiting intestinal absorption of cholesterol.
U.S. Pat. No. 4,868,210, issued to Trivedi on Sep. 19, 1989, as well as U.S. Pat. No. 4,923,896, May 8, 1990, disclose certain N-2,6-dialkyl- or N-2,6-dialkoxyphenyl-N'-arylalkyl ureas as potent inhibitors of ACAT.
European Patent Application 354,994, filed by Meguro and Ikeda which published on Feb. 21,1990, discloses certain N-aryl-N'-quinolin-4-yl ureas as ACAT inhibitors. European Patent Application 370,740, filed by Jackson et al. which published on May 30, 1990, discloses ACAT inhibitors similar in composition to those of deVries (vide supra) but different in constitution.
Billheimer, et al., European Patent Application EP-A-372,445, published on Jun. 13, 1990, discloses compounds of the formula: ##STR1## wherein
R.sup.1 and R.sup.2 are selected independently from H, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl, 2-, 3- or 4-pyridinyl, 2-thienyl, 2-furanyl, phenyl optionally substituted with 1 to 3 groups selected from F, Cl, Br, OH, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, CH.sub.3 S(O).sub.r, NO.sub.2, CF.sub.3 or NR.sup.7 R.sup.8 ; or
R.sup.1 and R.sup.2 can also be taken together as ##STR2## where L is O, O(CH.sub.2).sub.m+1 O or (CH.sub.2).sub.m where m is 0-4; R.sup.3 is H, C.sub.1 -C.sub.6 alkyl, allyl, benzyl or phenyl optionally substituted with F, Cl, CH.sub.3, CH.sub.3 O or CF.sub.3 ; PA0 R.sup.4 is straight chain C.sub.1 -C.sub.8 alkyl optionally substituted with F; C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; 2-, 3- or 4-pyridinyl, pyrimidinyl or biphenyl; PA0 R.sup.5 is H, C.sub.1 -C.sub.6 alkyl or benzyl; R.sup.6 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; pentafluorophenyl, benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, NH.sub.2, OH, CN, CO.sub.2 H, CF.sub.3, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.7 R.sup.8 or NCOR.sup.7 ; PA0 R.sup.7 and R.sup.8 are selected independently from H or C.sub.1 -C.sub.4 alkyl; PA0 X is S(O)r, O, NR.sup.5, CH.sub.2 ; PA0 A is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl or C.sub.3 -C.sub.10 alkynyl; PA0 Y is O, S, H.sub.2, NH; PA0 Z is NHR.sup.4, OR.sup.4 or R.sup.4 ; PA0 r is O-2, PA0 or a pharmaceutically acceptable salt thereof. PA0 A is alkylene of 7-20 carbon atoms of an alkenyl residue thereof with no more than 2 double bonds; PA0 R.sup.3 is H, CH.sub.3, of C.sub.2 H.sub.5 ; and PA0 n is 0, 1 or 2, such as 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoic acid ethyl ester. PA0 R.sup.7 is H, alkali metal ion, alkyl of 1 to 6 carbon atoms or benzyl; and PA0 n is 0 to 10. PA0 R.sup.1, R.sup.2 and R.sup.3 independently are H, F, Cl, CH.sub.3, CH.sub.30 or CF.sub.3 ; PA0 R.sup.4 is H, Na, K, CH.sub.3, CH.sub.3 CH.sub.2, (CH.sub.3).sub.2 CH, CH.sub.3 (CH.sub.2).sub.2 or butyl; PA0 A is C(CH.sub.3).sub.2, CH(CH.sub.2).sub.m CH.sub.3, (CH.sub.2)n or (CH.sub.2).sub.n-2 CH(CH.sub.3); PA0 m is 0 to 8; and PA0 n is 2 to 10. PA0 R.sup.6 and R.sup.7 independently are H, OH, saturated or unsaturated alkyl, cycloalkyl or hydroxyalkyl of 1 to 10 carbon atoms, ##STR8## R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 independently are H, F, Cl, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3, and alkoxy of 1 to 3 carbon atoms, with the proviso that R.sup.8 and R.sup.9, R.sup.10 and R.sup.11 or R.sup.12 and R.sup.13 taken together represent methylenedioxy; PA0 R.sup.14 is alkyl of 1 to 2 carbon atoms; PA0 m and n taken together represent a whole number from to 9; PA0 p is 0 to 2; PA0 s is 0 to 2; and PA0 t is 0 or 2. PA0 R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5 or alkyl of 1 to 9 carbon atoms; PA0 R.sup.6 is alkyl, cycloalkyl or hydroxyalkyl of 1 to 20 carbon atoms, H, alkali metal if X is --COO--, 1-phenethyl or ##STR11## R.sup.7 is H, OH if X is --CONR.sup.7 or alkyl of 1 to 4 carbon atoms; R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are independently H, Cl, F, Br, NO.sub.2, CH.sub.3 CONH, OH, alkyl of 1 to 3 carbon atoms, CF.sub.3 or alkoxy of 1 to 3 carbons or R.sup.8 and R.sup.9 or R.sup.10 and R.sup.11 taken together represent methylenedioxy; PA0 X is a bond, O, OC(.dbd.O)O, C(.dbd.O)O, CONR.sup.7, OC(.dbd.O) or OC(.dbd.O)NR.sup.7 ; PA0 m and n taken together represent a whole number from to 9; PA0 p is 0 to 2; PA0 s is 0 to 2; and PA0 t is 0 or 2. PA0 X.sub.1 is H, lower alkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino or ##STR13## X.sub.2 is H or when X.sub.1 is lower alkyl, lower alkyl or halogen; k is 0 to 2; PA0 m is 2 or 3, provided that the sum of k and m is 3 or 4; PA0 Y is O, S or NH; PA0 E is NR.sup.2 ; PA0 R.sup.1 is H, lower alkyl or di-lower alkyl amino-lower alkyl; and PA0 R.sup.2 is H, nitro or cyano. PA0 X.sub.1 and X.sub.2 may be H, lower alkyl, trifluoromethyl, hydroxyl, halogen, amino or X.sub.1 and X.sub.2 and at least two of the atoms comprising A may form a further ring; PA0 k is 0 to 2; PA0 m is 2 or 3, provided that the sum of k and m is 3 or 4; PA0 E is O, S or NR.sup.2 ; PA0 R.sup.1 is H, lower alkyl, acyl or dialkylaminoalkyl; and PA0 R.sup.2 is H, NO.sub.2, CN, alkanesulfonyl or arenesulfonyl. PA0 Q is NH, NCH.sub.3, O or S; PA0 X is S(O)r, O, NR.sup.5 or CH.sub.2 ; PA0 J is C.sub.2 -C.sub.10 alkyl, C.sub.3 -C.sub.10 branched alkyl, C.sub.3 -C.sub.10 alkenyl or C.sub.3 -C.sub.10 alkynyl; PA0 Y is O, S, H.sub.2 or NH; PA0 Z is NHR.sup.4, OR.sup.4 or R.sup.4 ; PA0 R.sup.1 and R.sup.2 are selected independently from H, Br, Cl, F, CF.sub.3, CN, NO.sub.2, CH.sub.3 S(O).sub.r, C.sub.1 -C.sub.8 alkyl or alkoxy, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; PA0 R.sup.3 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.3 -C.sub.8 alkenyl or alkynyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; 2-, 3- or 4pyridinyl, pyrimidinyl; or biphenyl; PA0 R.sup.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.4 -C.sub.10 cycloalkylalkyl, C.sub.3 -C.sub.6 alkenyl or alkynyl, C.sub.1 -C.sub.3 perfluoroalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, C.sub.3 -C.sub.8 branched alkyl, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, C.sub.3 -C.sub.8 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, C.sub.3 -C.sub.8 branched alkyl, F, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; 2-, 3- or 4- pyridinyl, pyrimidinyl; or biphenyl; PA0 R.sup.5 is H, C.sub.1 -C.sub.6 alkyl or benzyl; PA0 R.sup.6 and R.sup.7 are selected independently from H or C.sub.1 -C.sub.4 alkyl; PA0 R.sup.8 is H, C.sub.1 -C.sub.6 alkyl or phenyl; PA0 r is 0 to 2; PA0 or a pharmaceutically acceptable salt thereof. PA0 NH or NCH.sub.3 ; PA0 X is S(O).sub.r ; PA0 J is C.sub.2 -C.sub.10 alkyl or C.sub.4 -C.sub.9 branched alkyl; PA0 Y is O; PA0 Z is NHR.sup.4 ; PA0 R.sup.1 and R.sup.2 are selected independently from H, NO.sub.2, C.sub.1 -C.sub.8 alkyl or alkoxy, C.sub.3 -C.sub.8 branched alkyl, C.sub.1 -C.sub.4 carboalkoxy, NR.sup.6 R.sup.7 or NR.sup.6 COR.sup.7 ; PA0 R.sup.3 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, NH.sub.2, NO.sub.2, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3 or di(C.sub.1 -C.sub.4)alkylamino; phenyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, NH.sub.2, NO.sub.2, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3 or di(C.sub.1 -C.sub.4)alkylamino; benzyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, NH.sub.2, NO.sub.2, Br, Cl, OH, CN, CO.sub.2 H, CF.sub.3 or di(C.sub.1 -C.sub.4)-alkylamino; 2-, 3- or 4- pyridinyl, pyrimidinyl; or biphenyl; PA0 R.sup.5 is H. PA0 X is S(O).sub.r ; PA0 J is C.sub.2 -C.sub.10 alkyl; PA0 R.sup.1 is selected from H, CH.sub.3 or NO.sub.2 ; PA0 R.sup.2 is H; PA0 R.sup.3 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, NH.sub.2, NO.sub.2 or di(C.sub.1 -C.sub.4) alkylamino; phenyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, NH.sub.2, NO.sub.2 or di(C.sub.1 -C.sub.4) alkylamino; benzyl optionally substituted with 1 to 3 groups selected from CH.sub.3, CH.sub.3 O, F, NH.sub.2, NO.sub.2 or di(C.sub.1 -C.sub.4)alkylamino; 2-, 3- or 4-pyridinyl, pyrimidinyl; or biphenyl; PA0 R.sup.4 is C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 branched alkyl, C.sub.7 -C.sub.14 araalkyl where the aryl group is optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, NH.sub.2, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy or di(C.sub.1 -C.sub.4) alkylamino; phenyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, NH.sub.2, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy or di(C.sub.1 -C.sub.4)alkylamino; benzyl optionally substituted with 1 to 3 groups selected from C.sub.1 -C.sub.4 alkyl or alkoxy, F, NH.sub.2, NO.sub.2, C.sub.1 -C.sub.4 carboalkoxy or di(C.sub.1 -C.sub.4)alkylamino; 2-, 3- or 4- pyridinyl, pyrimidinyl; or biphenyl. PA0 N-[5-(1H-Benzimidazol-2-ylthio)pentyl]-N'-(2,4-difluorophenyl)-N-heptylurea PA0 N'-(2,4-Difluorophenyl)-N-heptyl-N[5-(6-nitro-1H-benzimidazol-2-ylthio)pent yl]urea PA0 N'-(2,4-Difluorophenyl)-N-heptyl-N-[5-(3H-imidazo[4,5-b]pyridin-2-ylthio)pe ntyl]urea PA0 N'-(2,4-Difluorophenyl)-N-heptyl-N-[5-(1-methyl-1H-benzimidazol-2-ylthio)pe ntyl]urea PA0 N'-(2,4-Difluorophenyl)-N-heptyl-N-[5-(4,5,6,7-tetrahydro-1H-benzimidazol-2 -ylthio)pentyl]urea PA0 N-Heptyl-N'-(1-methylethyl)-N-[5-(2,3,6,9-tetrahydro-1,3-dimethyl-2,6-dioxo -1H-purin-8-ylthio)pentyl]urea
These compounds are potent in vitro inhibitors of ACAT and are therefore potential antihypercholesterolemic agents.
U.S. Pat. No. 4,900,744, issued to Billheimer et al. on Feb. 13, 1990, discloses antihypercholesterolemic thioimidazoles of the formula: ##STR3## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 and R.sup.2 independently are H, F, Cl, CF.sub.3, alkyl of to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
U.S. Pat. No, 4,460,598, issued to Lautenschlager et al. on Jul. 17, 1984, discloses compounds of the formula: ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 independently are H, F, Cl, Br, I, alkyl, alkoxy or CF.sub.3, with the proviso that one or several of R.sup.1 and R.sup.2, R.sup.3 and R.sup.4 or R.sup.5 and R.sup.6 taken together represent methylenedioxy;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory and/or atherosclerotic diseases is disclosed.
U.S. Pat. No. 4,654,358, issued to Lautenschlager et al on Mar. 31, 1987, discloses compounds of the formula: ##STR5## wherein k is 0, 1 or 2,
The synthesis and the use of these compounds in the treatment of inflammatory diseases, diseases of lipid metabolism, and/or hyperlipidemic diseases is disclosed.
German Laid Open Application No. DE 3504679, Lautenschlager et al., published Aug. 14, 1986, discloses compounds of the formula: ##STR6## wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms or ##STR7## R.sup.4 and R.sup.5 independently are H, C.sub.6 H.sub.5 or alkyl of 1 to carbon atoms;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
German Laid Open Application No. DE 3504680, Lautenschlager et al., published Aug. 14, 1986, discloses compounds of the formula: ##STR9## wherein R.sup.1, R.sup.2 and R.sup.3 independently are H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 1 to 6 carbon atoms or ##STR10## R.sup.1 and R.sup.2 can be taken together with the carbon atoms in the 4 and 5 position of the imidazole ring to represent a carbocyclic five- or six-membered aromatic or partially hydrogenated ring which may be substituted by R.sup.8 or R.sup.9 ;
The synthesis and the use of these compounds in the treatment of thromboembolic, inflammatory, atherosclerotic, and lipid metabolism diseases in general is disclosed.
Durant et al., U.S. Pat. 4,228,291, issued Oct. 14, 1980, teaches compounds of the formula: ##STR12## wherein A together with the carbon atom form an unsaturated heterocyclic nucleus which may be an imidazole, pyrazole, pyrimidine, pyrazine, pyridazine, thiazole, isothiazole, oxazole, isoxazole, triazole, thiadiazole, benzimidazole or 5,6,7,8-tetrahydro-imidazol[1,5-a]pyridine ring;
The compounds are said to be antihistamines of the H.sub.2 receptor blocking type, as well as having anti-inflammatory activity.
White, U.S. Pat. 4,413,130, Nov. 1, 1983, discloses histamine H.sub.2 receptor antagonists of the formula: ##STR14## wherein: A together with the carbon atom form an unsaturated heterocyclic nucleus which may be an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, pyrazole, triazole, thiadiazole, pyrimidine, pyrazine or pyridazine;
There are no known literature references disclosing the compounds of this invention, their use as ACAT inhibitors or their use to lower cholesterol or in the treatment of atherosclerosis.
The compounds of this invention are very potent ACAT inhibitors, and thus are expected to be useful in pharmaceutical formulations for the treatment of atherosclerosis. This invention should not be construed as limited to any particular antihypercholesterolemic mechanism of action.